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J Biol Chem. 2019 Oct 25;294(43):15623-15637. doi: 10.1074/jbc.RA118.005729. Epub 2019 Aug 21.

Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge.

Author information

1
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853.
2
Center for Animal Resources and Education, Cornell University, Ithaca, New York 14853.
3
Department of Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, New York 14853.
4
Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, Tennessee 37996.
5
Department of Animal Science, Cornell University, Ithaca, New York 14853.
6
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853 rsw26@cornell.edu.

Abstract

Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2 -/- and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2 -/- mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2 -/- mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.

KEYWORDS:

DNA damage response; Fanconi anemia; Fanconi anemia complementation group D2 (FANCD2); cholestasis; cholesterol metabolism; fatty acid metabolism; lipid metabolism; liver metabolism; metabolic syndrome; nonalcoholic fatty liver disease

PMID:
31434739
PMCID:
PMC6816084
[Available on 2020-10-25]
DOI:
10.1074/jbc.RA118.005729

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